Introduction: One of the main causes of illness, mortality, and rising medical costs is antimicrobial resistance, which is a global healthcare concern. Objectives: This study explores the practice of physicians toward the effective implementation of Antibiotic Stewardship Programs (ASPs) in Najran city, Saudi Arabia. Methodology: This cross-sectional study was conducted among physicians working at primary care setting in Najran city, Saudi Arabia, between May and August 2023. A self-administered questionnaire was distributed among the physicians composed of three parts: socio-demographic data, a questionnaire about physicians’ practice in the efficacy of ASP, and a questionnaire about physicians’ practice regarding prescribing antibiotics. Results: Of the 128 physicians who participated in the study, 60.2% were males, and 43.8% were aged between 36 and 45 years. Among the practices in implementing the ASP effectively, controlling the source of infection domain received the highest score (mean score: 4.83). Every practice domain mean score was greater than 3, indicating that study participants possessed a moderate level of ASP practice and implementation skills. The overall mean practice score in the effective implementation of ASP was 154.9 ± 25.5 out of 185 points, with good, moderate, and poor practices constituting 67.2%, 28.1%, and 4.7%, respectively. Conclusions: The physicians showed a moderate level of practice for the effective implementation of ASPs in Najran city. The factors significantly associated with increased practice score include older age, male gender, Saudi nationality, handling five or fewer infection cases daily, and infection-initiated antibiotic prescribing treatment managed per day. These findings suggest the need for targeted interventions and educational programs to enhance physicians’ adherence to ASP guidelines and promote appropriate antibiotic prescribing practices, ultimately contributing to global efforts in combating antimicrobial resistance and improving patient outcomes.